JP2008525321A - Pain therapy - Google Patents

Abstract

The present invention is directed to methods and compositions for inducing, promoting, or otherwise promoting pain relief. More specifically, the present invention discloses the combination of nitric oxide donors and opioid analgesics in the therapeutic management of vertebrates, including humans, for the prevention or alleviation of pain, particularly moderate to severe pain. . In particular, the nitric oxide donor is a sustained release nitric oxide donor or is formulated to provide sustained release of low doses of nitric oxide.

Description

The present invention relates generally to methods for inducing, promoting, or otherwise promoting pain relief. More specifically, the present invention relates to the combined use of nitric oxide donors and opioid analgesics in the therapeutic management of vertebrates, including humans, for the prevention or reduction of pain, particularly moderate to severe pain. In particular, the nitric oxide donor is a sustained release nitric oxide donor or is formulated to provide sustained release of low doses of nitric oxide.

BACKGROUND OF THE INVENTION Opioid analgesics are the most effective class of drugs that can be used for pain management. Morphine is a powerful opioid analgesic that provides a “criteria” for comparing all new opioid analgesics. Morphine is also recommended by the World Health Organization as a drug of choice for moderate-to-severe cancer pain relief in moderate-to-severe pain in the post-surgical environment, and pain relief after trauma and myocardial infarction Has been.

  However, opioid analgesics including morphine are well documented to cause a variety of undesirable side effects. Serious side effects include allergic reactions such as dyspnea, swelling of the lips, tongue, face and / or throat, and hives; respiratory distress; seizures; cold skin; extreme weakness, extreme dizziness; Can be mentioned. Other side effects include sedation, nausea, vomiting, dry mouth, decreased appetite, constipation, dizziness, fatigue, consciousness, muscle spasms, sweating, pruritus, urinary retention, and decreased libido. In addition, long-term use of opioid analgesics may present tolerance, which increases the amount of opioid analgesic needed to obtain a certain level of pain relief. Some opioid analgesics, such as morphine, can be patient dependent with medium or long-term use.

  There is a need for a therapy that delivers pain relief from opioid analgesics with reduced side effects. There is also a need for therapies that reduce opioid analgesic consumption and still provide sufficient pain relief.

SUMMARY OF THE INVENTION The present invention shows that very low biological concentrations of nitric oxide increase the pain relief efficacy of opioid analgesics and / or the duration of analgesia achieved by opioid analgesics, thereby providing a given Predicted based in part on the conclusion that an amount of opioid analgesic can achieve long-term pain relief or reduce the amount of opioid analgesic used to achieve a given level of pain relief.

  Accordingly, in one aspect of the invention, the subject comprises administering an effective amount of a nitric oxide donor and an effective amount of an opioid analgesic, wherein the effective amount of the nitric oxide donor is 0.0002 nmol / kg. A method of producing analgesic effects in a subject is provided that delivers nitric oxide at a rate of from / nm to 2.0 nmol / kg / hour. Preferably, the nitric oxide donor is a sustained release nitric oxide donor or is formulated into a sustained release formulation.

  In another aspect of the present invention, the subject includes administering an effective amount of a nitric oxide donor formulated in a sustained release formulation and an effective amount of an opioid analgesic, the nitric oxide donor sustaining. The release formulation provides a method of producing analgesia in a subject that delivers nitric oxide at a rate of 0.0002 nmol / kg / hr to 2.0 nmol / kg / hr.

  In yet another aspect of the invention, the subject comprises administering to the subject an effective amount of a sustained release nitric oxide donor and an effective amount of an opioid analgesic, wherein the effective amount of the sustained release nitric oxide donor is A method of producing an analgesic effect in a subject that is in the range of 0.004 nmol / kg to 0.4 nmol / kg is provided.

  In another aspect, the invention comprises administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and a sub-analgesic amount of an opioid analgesic. A method of producing an analgesic effect in a subject is provided.

In another aspect, the invention includes administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and an effective amount of an opioid analgesic, comprising a nitric oxide donor Provides a method of producing analgesia in a subject that releases nitric oxide in the form of NO ⁺ or NO ⁻ .

  In yet another aspect, the invention includes administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and an effective amount of an opioid analgesic. The body provides a method of producing analgesic effects that enhances the endogenous production of nitrosothiols.

  In another aspect, the invention includes administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and an effective amount of an opioid analgesic, comprising a nitric oxide donor Provides a method of producing analgesic action that reduces endogenous production with peroxynitrite.

  In yet another aspect, the invention includes administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and an effective amount of an opioid analgesic. Provide a method of producing an analgesic effect in which the body causes more endogenous production of nitrosothiols than endogenous production of peroxynitrite.

  In a preferred embodiment, an effective amount of nitric oxide donor is compared to the ratio of nitrosothiol concentration: peroxynitrite concentration observed upon administration of a 5 mg nitroglycerin / 24 hour sustained release formulation of nitroglycerin. Increase the ratio of nitrosothiol concentration: peroxynitrite concentration in body fluids such as blood, serum, plasma, lymph, cerebrospinal fluid or brain extracellular fluid by at least 1.1 times.

  Sustained release nitric oxide donors are administered simultaneously, separately or sequentially with opioid analgesics to achieve analgesia. The nitric oxide donor sustained release formulation is administered simultaneously and / or separately with the opioid analgesic to achieve analgesia. Opioid analgesics may be administered in analgesic amounts or in sub-analgesic amounts. The nitric oxide donor and the opioid analgesic are suitably administered in the form of one or more compositions each containing a pharmaceutically acceptable carrier and / or diluent. The composition may be tested for a period of time by infusion, topical administration, subarachnoid administration, epidural administration, intraventricular administration, buccal administration, rectal administration, transdermal administration, or oral administration including sustained release modes of administration. It may be administered in an amount effective to produce an analgesic effect in the body.

  The sustained release nitric oxide donor is suitably selected from any substance that is converted or degraded or metabolized to or provides a source of nitric oxide in vivo over time. In one embodiment, the sustained release nitric oxide donor comprises a nitrato group attached to the carrier compound by a linker.

  The opioid analgesic is suitably selected from any opioid compound having analgesic activity. In one embodiment, the opioid analgesic is morphine, methadone, fentanyl, sufentanil, alfentanil, hydromorphone, oxymorphone, oxycodone, codeine, hydrocodeine, hydrocodone, levorphanol, meperidine, heroin, morphine-6-glucuronide, levalorphan , 6-monoacetylmorphine and tramadol.

  In another aspect, the invention includes administering an effective amount of a nitric oxide donor and an effective amount of an opioid analgesic, wherein the nitric oxide donor is a sustained release nitric oxide donor, or 0.0002 Provided is a method for alleviating pain formulated into a sustained release formulation that delivers nitric oxide at a rate of nmol / kg / hr to 2.0 nmol / kg / hr. In particular, these methods include nociceptive pain, such as moderate to severe cancer pain, moderate to severe postoperative pain, trauma from physical injury or moderate to severe pain caused by myocardial infarction, and Suitable for alleviating inflammatory pain conditions such as arthritis.

  In yet another aspect, the invention relates to the manufacture of a single agent or separate agents for use in combination therapy to produce analgesic action and / or to alleviate moderate to severe pain. Provided is the use of a nitric oxide donor and an opioid analgesic, wherein the nitric oxide donor is a sustained release nitric oxide donor, or between 0.0002 nmol / kg / hr to 2.0 nmol / kg / hr Formulated into sustained release formulations that deliver nitric oxide at a rate.

Detailed Description of the Invention Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Have. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. For purposes of the present invention, the following terms are defined as follows:

  The articles “a” and “an” indicate one or more (ie, at least one) grammatical objects of that article. For example, “an element” means one or more elements.

  As used herein, the term “about” refers to a quantity, level, value that varies by 30%, 20%, or 10% with respect to the quantity, level, value, dimension, size, or quantity mentioned. , Dimensions, size, or quantity.

As used herein, the term “alkyl” used alone or in compound words refers to a saturated straight chain, branched or cyclic hydrocarbon group, preferably C _1-20 alkyl, such as C _{1- 10} or C _1-6 is indicated. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl and its branched isomers, n-hexyl and its branched isomers, n -Heptyl and its branched isomers, n-octyl and its branched isomers, n-nonyl and its branched isomers, and n-decyl and its branched isomers. Examples of cyclic alkyl include monocyclic or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. The alkyl group may be further substituted with one or more optional substituents as defined herein.

As used herein, the term “alkenyl” refers to at least one carbon-carbon containing an ethylenated, mono-, di-, or poly-unsaturated alkyl or cycloalkyl group as defined above. It represents a straight, branched or cyclic hydrocarbon residue containing a double bond, preferably C _2-20 alkenyl (eg C _2-10 or C _2-6 ). Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl , Cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, Examples include, but are not limited to, 1,3-cyclopentadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, and 1,3,5,7-cyclooctatetraenyl. Not. An alkenyl group may be substituted by one or more optional substituents as defined herein.

As used herein, the term “alkynyl” refers to at least one carbon-carbon containing an ethyne, mono-, di-, or poly-unsaturated alkyl or cycloalkyl group as defined above. Indicates a straight, branched or cyclic hydrocarbon residue containing a triple bond. The term preferably denotes _C2-20 alkynyl. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be substituted by one or more optional substituents as defined herein.

The term “acyl” refers to a group containing a C═O moiety (but not a carboxylic acid, ester, or amide). Preferred acyl groups include C (O) -R, where R is hydrogen or an alkyl, alkenyl, alkynyl, aryl or heterocyclyl residue, preferably a _C1-20 residue. Examples of acyl groups are formyl; linear or branched alkanoyl, eg acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl , Dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as eg Benzoyl, toluoyl and naphthoyl; aralkanoyl, eg phenylalkanoyl (eg phenylacetyl, Phenylpropanoyl, phenylbutanoyl, phenylisobutyryl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (eg naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl); aralkenoyl, eg phenylalkenoyl (eg phenylalkenoyl) Propenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl) and naphthylalkenoyl (eg naphthylpropenoyl, naphthylbutenoyl and neftylpentenoyl); aryloxyalkanoyl, eg phenoxyacetyl And phenoxypropionyl; heterocyclic carbonyl; heterocyclic alkanoyl, eg thienylacetyl, thienylpropanoyl, thienylbutanoyl , Thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; and heterocyclic alkenoyl such as heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl and heterocyclic hexenoyl.

  As used herein, the terms “alkoxy”, “aryloxy”, “alkenyloxy”, “alkynyloxy”, “acyloxy”, and “heterocyclyloxy” are oxygen-bonded, Indicates an alkyl, aryl, alkenyl, alkynyl, acyl, or heterocyclyl group as defined in the specification.

  As used herein, the terms “alkylthio”, “alkenylthio”, “alkynylthio”, “arylthio”, “acylthio”, or “heterocyclylthio” are those connected by a sulfur atom. An alkyl, alkenyl, alkynyl, aryl, acyl, or heterocyclyl group, as defined

  As used herein, the terms “alkylamino”, “alkenylamino”, “dialkylamino”, “alkenylamino”, “arylamino”, “diarylamino”, “acylamino”, and “heterocyclylamino” Represents one or two alkyl or aryl groups or alkenyl, alkynyl, acyl or heterocyclyl groups as defined herein, which are connected by an NH or N atom.

As used herein, the term “aryl” refers to a C ₆ -C ₁₄ aromatic hydrocarbon group. Suitable aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl and phenanthrenyl. Preferred aryl groups include phenyl and naphthyl. The aryl group may be further substituted with one or more optional substituents.

  The term “analgesic” is used herein to describe a state in which pain perception is reduced and includes a state in which there is no pain sensation, as well as a reduction or absence in perception of noxious stimuli. Such a state of reduced or absent pain perception is caused by the administration of pain control agents, also called “analgesics”, without loss of consciousness, as is commonly understood in the art. The term analgesic includes the term “anti-nociceptive”, which is used in the art as a quantitative measure of analgesic or reduced pain sensitivity in animal models.

  Throughout this specification, unless the context requires otherwise, the terms `` comprise '', `` comprises '', and `` comprising '' are intended to refer to a given stage or It should be understood that includes an element or steps or elements but does not exclude one or more other steps or elements.

  In the context of pain treatment or prevention, an “effective amount” refers to a single dose or as part of a series of doses effective to prevent pain, prevent pain, and / or treat existing pain Means administration of an active amount to an individual in need of such treatment or prevention. The effective amount will vary depending on the health and physical condition of the individual to be treated, the taxon of the individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. The amount is expected to be within a fairly wide range that can be determined by routine testing.

  As used herein, the term “halo” is intended to include fluoro, chloro, bromo and iodo substituents.

  The term `` heterocyclyl '' refers to a monocyclic, polycyclic or fused, saturated, unsaturated or aromatic hydrocarbon residue, wherein one or more carbon atoms (and optionally attached thereto) Hydrogen atom) is replaced by a heteroatom. Suitable heteroatoms include O, N, S, and Se. Where two or more carbon atoms are substituted, this may be substituted by two or more of the same or different heteroatoms. Suitable examples of heterocyclic groups include pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, morpholino, indolinyl, imidazolidinyl, pyrazolidinyl, thiomorpholino, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, pyridyl, thienyl, furyl, pyrrolyl, Indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. The heterocyclyl group may be further substituted with one or more optional substituents as defined herein.

  “Nociceptive pain” refers to normal acute nociception induced by activation of nociceptors located in uninjured undamaged skin, internal organs and other organs.

  By “opioid analgesic” is meant an agent that binds to specific opioid receptors and activates those receptors to reduce or eliminate pain perception without causing loss of consciousness. Opioid analgesics include opiate alkaloids and their synthetic derivatives or analogs that may be isolated from opium.

  As used herein, “optionally substituted” means that the group is alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, Haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino , Dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, aryl Sulfenyloxy, heterocyclyl, heterocyclyloxy, heterocyclylamino, haloheterocyclyl, alkylsulfenyl, arylsulfenyl, carboalkoxy, carboaryloxy, mercapto, alkylthio, alkenylthio, alkynylthio, arylthio, benzylthio, heterocyclylthio, acylthio, cyano It is taken to mean that it may be further substituted or not substituted by one or more groups selected from nitro, sulphate and phosphate groups.

As used herein, the term “pain” is given its broadest meaning and is associated with or explained in terms of actual or potential tissue damage Including experience, including varying degrees of localized discomfort, distress, or agony, due to special nerve ending stimulation. There are many types of pain, including but not limited to electric shock, fantasy pain, throbbing pain, acute pain, inflammatory pain, neuropathic pain, complex local pain, neuralgia, neuropathy, etc. not (Dorland's Illustrated Medical Dictionary, 28 th Edition, WB Saunders Company, Philadelphia, Pa). The goal of pain treatment is to reduce the severity of pain perceived by the treated subject.

  By “pharmaceutically acceptable carrier” is meant a solid or liquid filler, diluent or encapsulating material that may be safely used in local, topical or systemic administration.

  As used herein, the term “pharmaceutically acceptable salts” refers to salts that are toxicologically safe for human and animal administration. This salt is, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, citrate, tartrate, bitartrate, phosphate, malate, maleate It may be selected from the group comprising acid salts, napsylates, fumarate, succinates, acetates, terephthalates, pamoates and pectates.

  The term “prodrug” is used in the broadest sense and includes compounds that are converted in vivo to opioid analgesics according to the present invention. Such compounds are easily conceived by those skilled in the art, and examples thereof include compounds in which a free hydroxy group is converted into an ester derivative. The prodrug form of the compound may be utilized, for example, to improve bioavailability, hide unpleasant properties such as bitterness, alter solubility for intravenous injection, or site specific of the compound Delivery may be provided.

  A “sustained release nitric oxide donor” or “sustained release NO donor” can be converted or degraded or metabolized to in vivo nitric oxide or NO over time or provide a source thereof, thereby reducing By any substance that delivers nitric oxide into the bloodstream. Suitably, the sustained release nitric oxide donor is delivered in an amount of 0.004 nmol / kg to 0.4 nmol / kg, or nitric oxide is delivered at a rate of 0.0002 nmol / kg / hour to 2.0 nmol / kg / hour. Administered in an amount.

  By “sub-analgesic dose” means the amount of an analgesic that, when administered alone, does not cause analgesia in a subject, but produces analgesia when administered in combination with an effective amount of a sustained release nitric oxide donor. .

  As used herein, the terms “subject” or “individual” or “patient” refer to any subject, particularly a vertebrate subject, more particularly a mammal, for which treatment or prevention is desired. Animal subjects are shown. Suitable vertebrates within the scope of the present invention include primates, birds, livestock (e.g. sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g. rabbits, mice, rats, guinea pigs, hamsters). ), Companion animals (eg, cats, dogs) and captive wild animals (eg, foxes, deer, dingos). A preferred subject is a human in need of treatment or prevention of pain, particularly moderate or severe pain. However, it will be understood that the terms do not imply that symptoms are present.

  As used herein, the term “sustained release formulation of nitric oxide donor” refers to 0.0002 nmol / kg / hour to 2.0 nmol / kg / hour, or 0.001 nmol / kg / hour to 1.0 nmol / kg / hour, 0.005 nmol / kg / hour to 1.0 nmol / kg / hour, 0.001 nmol / kg / hour to 0.5 nmol / kg / hour, 0.002 nmol / kg / hour to 0.2 nmol / kg / hour, 0.005 nmol / kg A nitric oxide donor formulation adapted to release nitric oxide at a rate in a range selected from: / hour to 0.1 nmol / kg / hour or 0.01 nmol / kg / hour to 0.05 nmol / kg / hour means. The sustained release formulation may be any formulation that can release nitric oxide at this rate. Preferred sustained release formulations are adapted to deliver 5 nmol to 500 nmol per 24 hours, especially 10 nmol to 100 nmol per 24 hours, more particularly 20 nmol to 60 nmol per 24 hours, most particularly 50 nmol per 24 hours. A transdermal patch.

How to cause analgesia
In one aspect, the present invention provides a method for producing analgesic action in a subject. These methods generally involve administration of an effective amount of a nitric oxide donor and an opioid analgesic, wherein the nitric oxide donor is a sustained release nitric oxide donor, or the nitric oxide donor is A sustained release formulation adapted to deliver nitric oxide at a rate of 0.0002 nmol / kg / hr to 2.0 nmol / kg / hr. The nitric oxide donor is administered in an amount that increases the pain relieving efficacy of the opioid analgesic or the duration of analgesia produced by the opioid analgesic. Opioid analgesics are administered in amounts that produce analgesic action when combined with a nitric oxide donor.

式中、
R¹はOH、OC_1〜6アルキル、-O-A-X-NO₂、

から選択され；
R²およびR³はそれぞれHであるか、または一緒に-O-となり；
R⁴はH、OH、OC_1〜6アルキル、-O-A-X-NO₂、

であり、かつR⁵はHであるか、あるいはR⁴およびR⁵は一緒にオキソ基を形成し；
R⁶はH、OH、OC_1〜6アルキル、-O-A-X-NO₂、

から選択され；
--------------は単結合または二重結合を示し；
XはOまたはSを示し；
YはO、S、SO、SO₂、CO、CONH、CO₂、NHまたはNC_1〜6アルキルを示し；
ZはSO、SO₂、CO、CONH、CO₂、NHまたはNC_1〜6アルキルを示し；
Aは下記を示し：

式中、Wは存在しないか、または-O-、-S-、-NH-、-NC_1〜6アルキル、

から選択され；
R⁷はC_1〜20アルキル、C_1〜20アルコキシ、C_1〜20アルキルCO、C_1〜20アルキルSO、C_1〜20アルキルSO₂、アリール、アリールオキシ、アリールSO₂、アリールSO、アリールCO、N(R⁸)₂、(R⁸)₂NCOから選択され；
各R⁸は、H、C_1〜20アルキル、C_2〜20アルケニル、C_2〜20アルキニルまたはアリールから独立して選択され、
各Rは、C_1〜20アルキル、C_2〜20アルケニル、C_2〜20アルキニル、アリール、ヘテロシクリル、ハロ、ヒドロキシ、C_1〜20アルコキシ、アリールオキシ、C_2〜20アルケニルオキシ、C_2〜20アルキニルオキシ、ヘテロシクリルオキシ、チオール、C_1〜20アルキルチオール、C_2〜20アルケニルチオール、C_2〜20アルキニルチオール、アリールチオール、ヘテロシクリルチオール、ベンジル、ベンジルオキシ、ベンジルチオ、アシル、アシルオキシ、CO₂R’、SOR’、SO₂R’、SO₃R’、SON(R’)₂、SO₂N(R’)₂、SO₃N(R’)₂、CON(R’)₂、N(R’)₂、P(R’)₃、P(=O)(R’)₃、Si(R’)₃、B(R’)₂C_1〜20アルキル、CN、CF₃またはNO₂から独立して選択され、式中、各R’はH、C_1〜20アルキル、C_2〜20アルケニル、C_2〜20アルキニル、アリールおよびヘテロシクリルから独立して選択され；
mは0または1〜10の整数であり；
nは1〜10の整数であり；および
tは0または1〜4の整数であり；
R¹、R⁴およびR⁶の少なくとも1つは-O-A-X-NO₂、

である。 The sustained release nitric oxide donor is selected from any substance that is converted or degraded or metabolized to or provides a source of in vivo nitric oxide over time. In one embodiment of the invention, the sustained release nitric oxide donor comprises a nitrato group attached to the carrier compound by a linker. Preferred sustained release nitric oxide donors include those of formula (I) or pharmaceutically acceptable salts thereof:

Where
R ¹ is OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
R ² and R ³ are each H or together become —O—;
R ⁴ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

And R ⁵ is H, or R ⁴ and R ⁵ together form an oxo group;
R ⁶ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

Wherein either W are not present, or -O -, - S -, - NH -, - NC 1~6 alkyl,

Selected from;
R ⁷ is C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkyl CO, C _1-20 alkyl SO, C _1-20 alkyl SO ₂ , aryl, aryloxy, aryl SO ₂ , aryl SO, aryl Selected from CO, N (R ⁸ ) ₂ , (R ⁸ ) ₂ NCO;
Each R ⁸ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl or aryl;
Each R is _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, aryl, heterocyclyl, halo, hydroxy, _C1-20 alkoxy, aryloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, heterocyclyloxy, thiol, C _{1 to 20} alkyl thiol, C _{2 to 20} alkenyl thiol, C _{2 to 20} alkynyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ R ' _{, SOR ', SO 2 R'} , SO 3 R ', SON (R') 2, SO 2 N (R ') 2, SO 3 N (R') 2, CON (R ') 2, N (R' ) ₂ , P (R ′) ₃ , P (═O) (R ′) ₃ , Si (R ′) ₃ , B (R ′) ₂ C _1-20 alkyl, CN, CF ₃ or NO ₂ Wherein each R ′ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, aryl and heterocyclyl;
m is 0 or an integer from 1 to 10;
n is an integer from 1 to 10; and
t is 0 or an integer from 1 to 4;
At least one of R ¹ , R ⁴ and R ⁶ is -OAX-NO ₂ ,

It is.

式中、
XはSまたはOであり；
pは1〜10の整数であり；および
qは0または1〜10の整数である。 Exemplary groups of formula -OAX-NO ₂ include the following:

Where
X is S or O;
p is an integer from 1 to 10; and
q is 0 or an integer of 1 to 10.

式中、
R¹⁰はOH、OCH₃、-O-A-X-NO₂、

から選択され；
R⁴⁰は-O-A-X-NO₂、

から選択され、かつR⁵⁰はHであるか、あるいはR⁴⁰およびR⁵⁰は一緒にオキソ基を形成し；
R⁶⁰はHまたは-O-A-X-NO₂、

から選択され；
--------------は単結合または二重結合を示し；
XはOまたはSを示し；
YはO、S、SO、SO₂、CO、CONH、CO₂、NHまたはNC_1〜6アルキルを示し；
ZはSO、SO₂、CO、CONH、CO₂、NHまたはNC_1〜6アルキルを示し；
Aは下記を示し：

式中、Wは存在しないか、あるいは-O-、-S-、-NH-、

から選択され；
R⁷⁰はC_1〜6アルキル、C_1〜6アルコキシ、C_1〜6アルキルCO、C_1〜6アルキルSO、C_1〜6アルキルSO₂、フェニル、フェノキシ、フェニルSO、フェニルSO₂、フェニルCO、N(R⁸⁰)₂および(R⁸⁰)₂NCOから選択され；
各R⁸⁰は、H、C_1〜6アルキル、C_2〜6アルケニル、C_2〜6アルキニルまたはアリールから独立して選択され；
各Rは、H、C_1〜6アルキル、C_2〜6アルケニル、C_2〜6アルキニル、アリール、ヘテロシクリル、ハロ、ヒドロキシ、C_1〜6アルコキシ、アリールオキシ、C_2〜6アルケニルオキシ、ヘテロシクリルオキシ、チオール、C_1〜6アルキルチオール、C_2〜6アルケニルチオール、アリールチオール、ヘテロシクリルチオール、ベンジル、ベンジルオキシ、ベンジルチオ、アシル、アシルオキシ、CO₂H、CO₂C_1〜6アルキル、SOC_1〜6アルキル、SO₂C_1〜6アルキル、SO₃H、SO₃C_1〜6アルキル、SONH₂、SONHC_1〜6アルキル、SON(C_1〜6アルキル)₂、SO₂NH₂、SO₂NHC_1〜6アルキル、SO₂N(C_1〜6アルキル)₂、CONH₂、CONHC_1〜6アルキル、CON(C_1〜6アルキル)₂、NH₂、NHC_1〜6アルキル、N(C_1〜6アルキル)₂、CN、CF₃またはNO₂から独立して選択され；
uは0または1〜5の整数であり；
vは1〜5の整数であり；および
tは0または1〜4の整数であり；
R¹⁰、R⁴⁰およびR⁶⁰の少なくとも1つは-O-A-X-NO₂、

である。 Preferred compounds include those of formula (II) or pharmaceutically acceptable salts thereof:

Where
R ¹⁰ is OH, OCH ₃ , -OAX-NO ₂ ,

Selected from;
R ⁴⁰ is -OAX-NO ₂ ,

And R ⁵⁰ is H or R ⁴⁰ and R ⁵⁰ together form an oxo group;
R ⁶⁰ is H or -OAX-NO ₂ ,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

In which W is absent or -O-, -S-, -NH-,

Selected from;
R ⁷⁰ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl CO, C _1-6 alkyl SO, C _1-6 alkyl SO ₂ , phenyl, phenoxy, phenyl SO, phenyl SO ₂ , phenyl CO N (R ⁸⁰ ) ₂ and (R ⁸⁰ ) ₂ NCO;
Each R ⁸⁰ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl;
Each R is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heterocyclyl, halo, hydroxy, C _1-6 alkoxy, aryloxy, C _2-6 alkenyloxy, heterocyclyloxy , Thiol, C _1-6 alkyl thiol, C _2-6 alkenyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ H, CO ₂ C _1-6 alkyl, SOC _1-6 Alkyl, SO ₂ C _1-6 alkyl, SO ₃ H, SO ₃ C _1-6 alkyl, SONH ₂ , SONHC _1-6 alkyl, SON (C _1-6 alkyl) ₂ , SO ₂ NH ₂ , SO ₂ NHC _{1 6 alkyl,} SO ₂ N (C 1~6 alkyl) _2, CONH _2, CONHC 1~6 alkyl, CON (C _{1 to 6} alkyl) _2, NH _2, NHC 1~6 alkyl, N (C _{1 to 6} Alkyl) ₂ , CN, CF ₃ or NO ₂ independently selected;
u is 0 or an integer from 1 to 5;
v is an integer from 1 to 5; and
t is 0 or an integer from 1 to 4;
At least one of R ¹⁰ , R ⁴⁰ and R ⁶⁰ is -OAX-NO ₂ ,

It is.

Examples of suitable sustained release nitric oxide donors include the following and their pharmaceutically acceptable salts:

Compounds of formula (I) may be prepared by synthetic methods known to those skilled in the art. Such methods, Advanced Organic Chemistry, March J, 3 rd Edition, John Wiley and Sons, 1985 and Comprehensive Organic Transformations, RC Larock, may be found in the body, such as VCH, 1989. It is also known in the art that functional groups may need to be protected and deprotected during the synthesis process. Suitable protection and deprotection methods are described in Protective Groups in Organic Chemistry, T .; W. It may be found in texts such as Greene and PGM Wuts, Wiley Interscience, 1999.

  A compound of formula (I) may be prepared by conjugating a commercially available morphine compound or derivative or a morphine derivative prepared from a commercially available compound with a nitrato, furazanyl or -SNO containing linker. For example, a linker containing a free carboxylic acid or acid chloride and a nitrato, furazanyl or —SNO group may be attached to the free hydroxy group of a morphine or morphine derivative by esterification methods well known in the art. For example, coupling may be achieved by treating carboxylic acid and morphine derivative hydroxy groups with a dehydrating agent such as dicyclohexylcarbodiimide (DCC). Alternatively, a linker containing a nitrato, furazanyl or —SNO group and a leaving group may be attached to free hydroxy to form an ether linkage.

  In another aspect of the invention, compounds of formula (I), pharmaceutically acceptable salts thereof, and compounds of formula (I), pharmaceutically acceptable salts thereof, and optionally opioid analgesics A composition comprising is provided.

  An effective amount of the nitric oxide donor is effective to enhance or increase the pain relief efficacy or duration of effect of the opioid analgesic. In one embodiment, the amount of sustained release nitric oxide donor administered as a bolus ranges from 0.004 nmol / kg to 0.4 nmol / kg, preferably from 0.005 nmol / kg to 0.3 nmol / kg, from 0.006 nmol / kg. 0.2 nmol / kg, 0.007 nmol / kg to 0.1 nmol / kg, 0.008 nmol / kg to 0.09 nmol / kg, 0.009 nmol / kg to 0.08 nmol / kg, 0.01 nmol / kg to 0.07 nmol / kg, 0.02 nmol / kg A range selected from 0.06 nmol / kg, particularly 0.03 nmol / kg to 0.05 nmol / kg. An especially preferred amount is 0.04 nmol / kg. In another embodiment, the nitric oxide donor is at a rate of 0.0002 nmol / kg / hour to 2.0 nmol / kg / hour, or 0.001 nmol / kg / hour to 1.0 nmol / kg / hour, 0.005 nmol / kg / hour. ~ 1.0 nmol / kg / hour, 0.001 nmol / kg / hour to 0.5 nmol / kg / hour, 0.002 nmol / kg / hour to 0.2 nmol / kg / hour, 0.005 nmol / kg / hour to 0.1 nmol / kg / hour, Alternatively, it is formulated into a sustained release formulation adapted to release nitric oxide within a range selected from 0.01 nmol / kg / hour to 0.05 nmol / kg / hour. A particularly preferred embodiment is a transdermal patch adapted to release 5 nmol to 500 nmol, especially 10 nmol to 100 nmol, more particularly 20 nmol to 60 nmol, more specifically about 50 nmol per 24 hours.

While not wishing to be bound by any one theory or mode of action, it is hypothesized that sustained release of NO from the nitric oxide donor maintains a low concentration of NO in the bloodstream. The sustained release of NO is thought to favor the formation of NO ⁺ , and possibly NO ⁻ , thought to be important in the endogenous formation of nitrosothiols. Sustained release of NO, superoxide (O ₂ ^-) and readily react, powerful neurotoxin, peroxynitrite (ONOO ^-) not work advantageously in the formation of NO ^· to generate.

Endogenous nitrosothiols promote the nitrosylation of the N-methyl-D aspartate receptor (NMDA receptor), thereby reducing the activation of this receptor and consequently hypothesized that the pain response is attenuated. The In one embodiment, an effective amount of a sustained release nitric oxide donor or sustained release formulation of nitric oxide donor is one that is effective to release NO in the form of NO ⁺ and NO ⁻ . In yet another aspect, an effective amount of sustained release nitric oxide donor or sustained release formulation of nitric oxide donor enhances endogenous production of nitrosothiol or reduces endogenous production of peroxynitrite. Or one that causes more endogenous production of nitrosothiols than endogenous production of peroxynitrite. Endogenous production of peroxynitrite may be assessed by measuring nitrotyrosine in body fluids.

  In yet another aspect, the effective amount of nitric oxide donor is compared to the ratio of nitrosothiol concentration: peroxynitrite concentration observed with administration of a sustained release formulation of nitroglycerin that delivers 5 mg of nitroglycerin per 24 hours. The ratio of nitrosothiol concentration in body fluid: peroxynitrite concentration is increased at least 1.1 times. In a preferred embodiment, the ratio of nitrosothiol concentration: peroxynitrite concentration is 1.25 to 100 times, preferably 1.25 compared to the ratio of nitrosothiol concentration: peroxynitrite concentration observed with administration of a sustained release formulation of nitroglycerin. It increases to ˜500 times, more preferably 1.25 to 1000 times. This ratio is 1.25-5 times, 1.25-10, 1.25-20, 1.25-30, 1.25-40, 1.25-50, 1.25-60, 1.25-70, 1.25-80, 1.25-90 or 1.25-100 times Increasing is particularly preferred.

  In biological systems, nitric oxide is stabilized by nitrosothiol formation, suggesting that its biological activity is preserved. Nitrosothiols have a significantly longer half-life than nitric oxide in vivo and also act as potent antiplatelet and vasodilators. The main nitrosothiol in mammalian plasma is nitrosoalbumin (AlbSNO), which then transfers nitric oxide to low molecular weight thiols such as glutathione (GSH) or cysteine (CySH), respectively, GSNO or CySNO, respectively. Is formed. The low molecular weight nitrosothiol can then diffuse to the desired site of action and release nitric oxide.

The level of nitrosothiols, such as AlbSNO, GSNO or CySNO, in the blood may be determined using a suitable assay. The level of peroxynitrite (ONOO ⁻ ) formed by the reaction of nitric oxide (NO) with superoxide (O ₂ ⁻ ) can be determined by monitoring the level of nitrotyrosine in body fluids. The amount of nitrosothiols, such as S-nitrosoglutathione (GSNO) and S-nitrosocysteine (CySNO), and nitrotyrosine can be measured in high-performance liquid chromatography electrospray ionization tandem mass spectrometry in body fluids, such as plasma ultrafiltrate (HPLC-ESI-MS-MS) Assays may be determined simultaneously using deuterated analogs of cysteine, glutathione and nitrotyrosine as internal standards. Chromatographic separation is achieved using Agilent Zorbax C18 2.1 x 50 mm column type with a moving bed containing component A (0.1% v / v formic acid) and component B (90:10 methanol water with 0.1% formic acid). . This method is derived from the method of Kluge et.al., (1997), J. Neurochem., 69: 2599-2607 and Orhan et. Al., (2004), J. Chrom. B., 799: 245-254. Is adapted

  The opioid analgesic may be any opioid compound having analgesic activity. In a preferred embodiment, the opioid analgesic is morphine, methadone, fentanyl, sufentanil, alfentanil, hydromorphone, oxymorphone, oxycodone, codeine, hydrocodeine, hydrocodone, levorphanol, meperidine, heroin, morphine-6-glucuronide, levalorphan, Selected from 6-monoacetylmorphine and tramadol.

  The dose of active compound administered to the patient should be sufficient to achieve a beneficial response in the patient over time, for example, a reduction or alleviation of pain. The amount of pharmaceutically active compound administered can depend on the subject being treated, including age, sex, weight, and general health. In this regard, the exact amount of active compound for administration will depend on the judgment of the physician. In determining the effective amount of active compound to be administered in producing analgesic action, the physician may assess the severity of pain symptoms associated with nociceptive pain or an inflammatory pain condition, and opioid analgesia. The amount of drug may take into account whether the patient is naive to opioid analgesics or if there has been a previous long-term exposure to opioid analgesics. In any event, one of ordinary skill in the art may readily determine a suitable dose of the nitric oxide donor and / or opioid analgesic of the present invention without undue experimentation.

  An effective amount of an opioid analgesic may be an amount that is a recommended dose for opioid naïve patients or for patients resistant to the opioid analgesic effect. For example, in adult morphine naïve patients, the standard dose is 5-20 mg when delivered by intramuscular or subcutaneous injection, or 2.5-15 mg when delivered by intravenous injection. Morphine may also be administered in oral rapid-acting tablets or capsules at a dose of 10-30 mg, or in a 40 mg or 20 mg oral sustained release dosage form. Morphine may also be administered to adult morphine naive patients by epidural administration (5 mg), subarachnoid administration (0.2-1 mg) or intracerebroventricular administration (0.1-1 mg). Suitable doses of morphine for administration to children include 0.1-0.2 mg / kg to up to 15 mg by intramuscular or subcutaneous injection, or, if dosed by intravenous administration, 5-15 It may be gradually increased over a period of 0.05 to 0.1 mg / kg. The above doses for intramuscular or subcutaneous injections or oral fast-acting tablets or capsules are usually administered at a frequency of every 4-6 hours, but when combined with a nitric oxide donor according to the invention, the frequency of administration is 5-7 hours, There may be an extension every 6-8 hours, 7-9 hours, 8-10 hours, 9-11 hours or 11-12 hours. The above dosage forms for oral sustained release formulations are usually given at a frequency of 40 mg / 24 hours or 20 mg / 12 hours, but these formulations are combined with nitric oxide donors according to the present invention at longer intervals, For example, it may be administered at 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 hours or 13, 14, 15, 16, 17 or 18 hours. The standard doses indicated above for epidural, subarachnoid or intracerebroventricular administration are usually given at a frequency of every 24 hours. However, when combined with a nitric oxide donor according to the present invention, the frequency of administration may be extended to, for example, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 hour intervals. .

  Standard oxycodone doses for adult opioid naïve patients include 1-10 mg by intravenous injection or 1-10 mg by intramuscular or subcutaneous injection. Oral administration may be in a 5-10 mg dose immediate release tablet or in a 10 mg sustained release oral dosage form. The oxycodone dose may also be administered at 30 mg by rectal suppository. The above oxycodone dose for intravenous, intramuscular or subcutaneous injection or oral immediate release tablets is usually administered every 4-6 hours, but when combined with a nitric oxide donor according to the present invention, the frequency of administration is: For example, it may be extended every 5-7 hours, 6-8 hours, 7-9 hours, 8-10 hours, 9-11 hours or 11-12 hours. A sustained release oral dose of oxycodone is usually given every 12 hours, but when combined with a nitric oxide donor according to the present invention, this frequency can be, for example, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or May be extended every 18 hours. Rectal suppository forms of oxycodone are usually given at a frequency of every 6-8 hours, but when combined with a nitric oxide donor according to the present invention, this frequency of administration is, for example, 7-9 hours, 8-10 hours, 9-9 There may be an extension every 11 hours, 10-12 hours, 11-13 hours, 12-14 hours, 13-15 hours or 14-16 hours.

  Standard hydromorphone doses for producing analgesia in opioid-naive patients include oral doses of 2-4 mg, 1-2 mg by intramuscular or subcutaneous injection, or 0.5-1.0 by intravenous delivery delivered over 2-3 minutes. mg. The frequency of administration of oral dosage forms is usually every 4 hours, but when combined with a nitric oxide donor according to the present invention, the frequency of administration is eg 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours. There is a possibility to be extended every hour. The frequency of administration of intramuscular or subcutaneous injection forms is usually every 2 hours. However, in combination with the nitric oxide donor according to the invention, this dosing frequency can be extended, for example, every 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours. Suitable doses for children include oral doses of 60 μg / kg or 15 μg / kg when delivered by intramuscular, subcutaneous or intravenous injection. The frequency of administration of hydromorphone for both oral and injection forms in children is usually every 3-4 hours. However, when combined with a nitric oxide donor according to the present invention, the frequency of administration is, for example, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 8-9 hours, or 9-10 hours. May be extended.

  Suitable doses of fentanyl to produce analgesia in adult opioid-naïve patients include 50-100 μg administered intramuscularly 30-60 minutes before surgery and, if necessary, intramuscularly after surgery. 50 to 100 μg. Post-operative fentanyl is often delivered every 1-2 hours, but when combined with a nitric oxide donor according to the present invention, the delivery frequency is, for example, 2-3 hours, 3-4 hours, 4-5 hours, May be extended to 5-6 hours, 6-7 hours, or 7-8 hours. Fentanyl may also be delivered by a transdermal patch at a dose of 25 μg / hour.

Alternatively, opioid analgesics may be administered in sub-analgesic amounts, which when administered alone do not cause analgesia in a subject but are administered in combination with an effective amount of a sustained release nitric oxide donor. Then, it is the quantity which produces an analgesic effect. For example, the sub-analgesic amount may be an ED ₁₀ -ED ₉₀ amount corresponding to a dose effective to produce an analgesic response in 10-90% of the patient or subject. Preferably, the sub-analgesic amount is ED _{10 to} ED ₈₀ , ED _{10 to} ED ₇₀ , ED _{10 to} ED ₆₀ , ED _{10 to} ED ₅₀ , ED _{10 to} ED ₄₀ , and especially ED _{10 to} ED _30. Corresponds to one of the quantities. An especially preferred sub-analgesic amount is the ED ₂₀ amount.

  The method for producing an analgesic action is suitable for use in the treatment of pain, particularly moderate to severe pain. The treatment is suitable for use in any situation where the use of opioid analgesics is usually indicated. For example, treatment may include nociceptive pain, such as moderate to severe cancer pain relief, moderate to severe pain relief in the post-operative environment, and physical trauma, such as pain after soft tissue injury after an accident. Suitable for use in the relief of pain associated with myocardial infarction, as well as the relief of inflammatory pain, eg joint pain.

If the amount of opioid analgesic administered is standard or analgesic (ED ₁₀₀ ) and is administered in combination with an effective amount of nitric oxide donor, the analgesic duration is the same amount of opioid analgesic administered alone Could be longer than what is experienced. This reduces the frequency with which opioid analgesics are administered to the subject, thus reducing the side effects experienced and / or reducing the severity of the side effects.

  When the amount of opioid analgesic administered is less than analgesic and is administered in combination with an effective amount of nitric oxide donor, the analgesic effect experienced is 1.5 to 5 times more dose, e.g. 3 times more dose. The same efficacy and duration as experienced when administered. This will result in administration of much lower arbitrary doses of opioid analgesics, thus reducing the side effects experienced and / or reducing the severity of the side effects. For example, any one or more of the following: decreased allergic reaction, eg, dyspnea, swelling of lips, tongue, face and / or throat, and disappearance or reduction of hives; loss or reduction of respiratory disorder, seizures Reduction or severity of seizures; reduction of cold skin, reduction of frailty, loss or dizziness of dizziness, reduction of possibility of loss of consciousness, reduction or disappearance of sedation, reduction or disappearance of nausea, vomiting or mouth Decreased or eliminated thirst, decreased or decreased appetite, decreased or eliminated constipation, reduced or eliminated fatigue, reduced or eliminated dizziness, reduced or eliminated muscle spasm, reduced or eliminated sweating, reduced or eliminated pruritus, Reduced or eliminated urinary retention and decreased libido. The likelihood of developing opioid analgesic tolerance or dependence may also be reduced.

  The effect of the combination of a sustained release nitric oxide donor and an opioid analgesic may be tested using one or more published models of pain / nociception known in the art. Analgesic activity is determined by methods known in the art, such as the Tail-flick test (D'Amour et. Al., 1941, J. Pharmacol. Exp. Ther. 72: 74-79), hot plates. Test (Eddy and Leimbach, 1953, J. Pharmocol. Exp. Ther., 107: 385-93), paw pressure test (Randall and Selitto, 1957, Arch. Int. Pharmacodyn., 111: 409-414 ), Paw thermal test (Hargreaves et. Al., 1998, Pain, 32: 77-88) and Brennan model of postoperative pain (Brennan et. Al., 1996, Pain, 64: 493-501) You may evaluate using.

  The nitric oxide donor and the opioid analgesic may be administered simultaneously in a single composition, or may be administered simultaneously or sequentially in separate doses as a non-mixed or undiluted compound However, it is more common to administer the compound in a pharmaceutical composition. Suitable compositions comprise an effective amount of active agent and a pharmaceutically acceptable carrier, diluent or excipient to achieve the purpose.

  In one embodiment, depending on the intended mode of administration, the nitric oxide donor-containing composition is generally about 0.1% to 90%, about 0.5% to 50%, or about 1% to about 25% by weight. % Nitric oxide donor, the remainder being a suitable pharmaceutical carrier and / or diluent, etc., optionally an opioid analgesic. The dose of nitric oxide donor may depend on various factors, such as individual nitric oxide donor, mode of administration, species of subject affected, age and / or individual condition.

  In another embodiment, the opioid analgesic-containing composition is generally about 0.1% to 90%, about 0.5% to 50%, or about 1% to about 25%, depending on the intended mode of administration. Of the opioid analgesic, the remainder being a suitable pharmaceutical carrier and / or diluent, etc., optionally a nitric oxide donor.

  Depending on the particular pain being treated, the active compound may be formulated and administered for systemic, topical or topical use. Techniques for formulation and administration may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., Latest edition. Suitable routes include, for example, oral, rectal, transmucosal, or enteral; intramuscular, subcutaneous, intramedullary injection, and subarachnoid, epidural, direct intraventricular, intravenous, intraperitoneal, inhalation, intranasal Or parenteral delivery including intraocular administration. For injection, the therapeutics of the invention may be suitably formulated in aqueous solutions, suitably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to penetrate the barrier are used in the formulation. Such penetrants are generally known in the art.

  Alternatively, the compositions of the invention can be formulated for topical or local administration. In this case, the subject compositions may be formulated in any suitable manner, including but not limited to creams, gels, oils, ointments, solutions and suppositories. Such topical compositions may contain penetration enhancers such as benzalkonium chloride, digitonin, dihydrocytochalasin B, capric acid and the pH is increased from 7.0 to 8.0. Penetration enhancers directed to promote penetration of the active compound through the epidermis are advantageous in this regard. Alternatively, the topical composition may comprise liposomes in which the active compound of the invention is encapsulated.

  The opioid analgesic and sustained release nitric oxide donor may be formulated in a single composition or may be formulated separately for simultaneous or sequential delivery by the same or different modes of administration. For example, opioid analgesics may be formulated for oral delivery, while nitric oxide donors are formulated to be delivered by transdermal patches, or opioid analgesics are formulated for parenteral administration. Whereas the sustained release nitric oxide donor is formulated for oral delivery, or both the opioid analgesic and the sustained release nitric oxide donor are a single composition or separate The composition may be formulated, or the nitric oxide donor may be formulated for transdermal delivery, while the opioid analgesic is formulated for parenteral administration. Other delivery mode combinations are readily determined by those skilled in the art.

  The compositions of the invention may be formulated for administration in the form of a liquid containing acceptable diluents (e.g., saline and sterile water) or may have the desired feel, consistency, viscosity, and appearance. It may be in the form of a lotion, cream or gel containing an acceptable diluent or carrier for application. Acceptable diluents and carriers are well known to those skilled in the art and include ethoxylated and non-ethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (e.g., palm oil, coconut oil, and mineral oil), Cocoa butter wax, silicone oil, pH balancer, cellulose derivatives, emulsifiers such as nonionic organic and inorganic bases, preservatives, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohols Examples include, but are not limited to, esters, hydrophilic lanolin derivatives, and hydrophilic beeswax derivatives.

  Alternatively, the active compounds of the present invention can be readily formulated into pharmaceutically suitable dosage forms suitable for the practice of the present invention using pharmaceutically acceptable carriers well known in the art. With such carriers, the compounds of the present invention can be formulated into dosage forms such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., so that the patient undergoing treatment can take them orally. it can. These carriers are free of saccharides, starch, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oil, synthetic oil, polyol, alginic acid, phosphate buffer, emulsifier, isotonic saline, and pyrogens You may choose from water.

  Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers, or agents that increase the solubility of the compound, allowing the preparation of highly concentrated solutions.

  Pharmaceutical preparations for oral use combine the active compound with solid excipients, optionally mill the resulting mixture and, if desired, add suitable auxiliaries before processing the granule mixture And obtaining a tablet or dragee core. Suitable excipients are in particular fillers such as sugars including lactose, sucrose, mannitol or sorbitol; for example corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose Cellulose preparations such as sodium and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Such compositions may be prepared by any pharmaceutical method; however, all methods comprise one or more therapeutic agents as described above and one or more necessary ingredients. A step of combining with a carrier to be treated. In general, the pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by conventional mixing, dissolving, grinding, dragee-forming, gelling, emulsifying, encapsulating, encapsulating or lyophilizing processes. Also good.

  Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which optionally include gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. May be included. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

  Formulations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-in capsules can contain the active ingredient as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally an oxidizing agent. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

  The active compound dosage forms of the invention may also include infusion or implant controlled release devices specifically designed for this purpose, or in addition to other types of implants modified to work in this way. Controlled release of the active compounds of the present invention can result in the compounds of the present invention having hydrophobic polymers including, for example, acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids, and certain cellulose derivatives such as hydroxy It may be achieved by coating with propylmethylcellulose. Moreover, controlled release may be achieved using other polymer matrices, liposomes and / or microspheres. Controlled release can also be embedded in a transdermal patch, particularly a biodegradable matrix in which the release rate of the nitric oxide donor is controlled by a copolymer release membrane or the nitric oxide donor dissolves at a known rate. May be achieved using existing transdermal patches. Transdermal patches are known in the art that are capable of delivering and sustained delivery of drugs at a known rate.

  The compounds of the present invention are based on a number of factors including the severity of the pain being treated, whether the pain is chronic, or whether there is a potential for recurrence of pain, etc. May be administered over a period of several weeks or months. Administration may be constant, for example, constant infusion over a period of hours, days, weeks, months, etc. Alternatively, administration may be intermittent, e.g., the active compound may be administered once a day for several days, once an hour, for several hours, or whatever is considered suitable Other such plans may be possible.

  The compositions of the present invention may also be used as a nasal or pulmonary inhalation aerosol or solution for nebulizers, as a fine powder for insufflation, alone or in combination with an inert carrier such as lactose, or other pharmaceutically acceptable. May be administered to the respiratory tract with other excipients. In such cases, it is convenient for the particles of the formulation to have a diameter of less than 50 μm, and less than 10 μm may be suitable.

  In order to easily understand the present invention and produce actual effects, particularly preferred embodiments will be described by the following non-limiting examples.

乾燥アセトン5mlに溶解したクロロ酢酸(1.89g、20mmol)の溶液に、乾燥アセトン10mlに溶解したNaI(30mmol、4.5g)の溶液を添加し、混合物を還流しながら、1時間加熱した。その後、溶媒を除去し、残渣を水10mlで処理した。混合物をジエチルエーテル(3×50ml)で抽出し、有機相を合わせ、塩類溶液、飽和Na₂S₂O₃溶液で洗浄し、Na₂SO₄上で乾燥させ、溶媒を真空で除去すると、2.8gの黄色固体が得られ、これをさらに精製せずに使用した。 Example Example 1
Preparation of morphine conjugate (2) Nitratoacetic acid (1)

To a solution of chloroacetic acid (1.89 g, 20 mmol) dissolved in 5 ml of dry acetone was added a solution of NaI (30 mmol, 4.5 g) dissolved in 10 ml of dry acetone and the mixture was heated at reflux for 1 hour. Thereafter, the solvent was removed and the residue was treated with 10 ml of water. The mixture was extracted with diethyl ether (3 × 50 ml), the organic phases were combined, washed with brine, saturated Na ₂ S ₂ O ₃ solution, dried over Na ₂ SO ₄ and the solvent removed in vacuo to yield 2.8. g of a yellow solid was obtained and used without further purification.

The solid was dissolved in 10 ml dry acetonitrile and a solution of AgNO ₃ (5.1 g, 30 mmol) dissolved in 20 ml acetonitrile was added. The mixture was stirred overnight at room temperature and a yellow precipitate formed. To this mixture was added 10 ml of saline solution and the mixture was removed by filtration. The filtrate was extracted with diethyl ether (3 × 50 ml), the organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and the solvent removed in vacuo to give a yellow solid (1.45 g, 12 mmol, 60%).

ニトラト酢酸(64mg、0.53mmol)を無水クロロホルム40mlに溶解し、新たに調製した遊離モルヒネ塩基(150mg、0.53mmol)およびジシクロヘキシルカルボジイミド(109mg、0.53mmol)をアルゴン雰囲気下で添加した。混合物を70℃まで10時間加熱した。その後、追加部分のニトラト酢酸(64mg)およびジシクロヘキシルカルボジイミド(109mg)を添加した。加熱を6時間続けた。その後、混合物を室温まで冷却し、溶媒を真空で除去した。残渣を水(20ml)で処理し、20分間撹拌した。その後、沈殿を濾過して除去し、水(2×10ml)で洗浄した。水溶液を真空で濃縮すると120mg(0.31mmol、59%)の(2)が褐色固体として得られた。 Morphine conjugate (2)

Nitratoacetic acid (64 mg, 0.53 mmol) was dissolved in 40 ml of anhydrous chloroform and freshly prepared free morphine base (150 mg, 0.53 mmol) and dicyclohexylcarbodiimide (109 mg, 0.53 mmol) were added under an argon atmosphere. The mixture was heated to 70 ° C. for 10 hours. An additional portion of nitratoacetic acid (64 mg) and dicyclohexylcarbodiimide (109 mg) was then added. Heating was continued for 6 hours. The mixture was then cooled to room temperature and the solvent removed in vacuo. The residue was treated with water (20 ml) and stirred for 20 minutes. The precipitate was then removed by filtration and washed with water (2 × 10 ml). The aqueous solution was concentrated in vacuo to give 120 mg (0.31 mmol, 59%) of (2) as a brown solid.

モルヒネ塩酸塩三水和物(1.5g)を最小量の水(RO型)(〜20mL)に溶解し、これに、十分な飽和炭酸水素ナトリウムを添加しモルヒネを沈殿させた。モルヒネ3を真空濾過により収集し、蒸留水(20mL)、続いて少量の冷ジエチルエーテル(5mL)で洗浄した。アルミ箔で遮光した白色固体を高真空下(0.01mmHg)に3時間置いた。 Example 2
Preparation of morphine-oxide conjugate 5
(a) Morphine

Morphine hydrochloride trihydrate (1.5 g) was dissolved in a minimum amount of water (RO type) (˜20 mL), and enough saturated sodium bicarbonate was added to precipitate morphine. Morphine 3 was collected by vacuum filtration and washed with distilled water (20 mL) followed by a small amount of cold diethyl ether (5 mL). The white solid shielded with aluminum foil was placed under high vacuum (0.01 mmHg) for 3 hours.

標題化合物をEP 0 984 012 A2(K.M.Lundy, M.T.Clark)の手順に従い調製した。簡単に言うと、硝酸銀(23.48g、0.153mol)を高真空(0.01mmHg)下、予め乾燥させ、その後、アルゴン雰囲気下、無水アセトニトリル(70mL)に溶解した。溶液を50℃まで温め、5-ブロモ吉草酸(5g、0.028mol)[無水アセトニトリル(3mL)に溶解]をシリンジによりすぐに添加した。即時に沈殿が形成した。混合物をその後80℃で20分間加熱した。冷却し、沈殿(AgBr)を濾過により除去した。濾液を濃縮し、残渣を酢酸エチルと水の間で分配させた。酢酸エチル層をその後水で洗浄し、乾燥させ(Na₂SO₄)、濃縮し、さらに真空下(0.01mmHg)で乾燥させた。標題化合物をさらに精製せずに使用した。 (b) 5-nitratovaleric acid

The title compound was prepared according to the procedure of EP 0 984 012 A2 (KMLundy, MTClark). Briefly, silver nitrate (23.48 g, 0.153 mol) was pre-dried under high vacuum (0.01 mmHg) and then dissolved in anhydrous acetonitrile (70 mL) under an argon atmosphere. The solution was warmed to 50 ° C. and 5-bromovaleric acid (5 g, 0.028 mol) [dissolved in anhydrous acetonitrile (3 mL)] was immediately added via syringe. A precipitate formed immediately. The mixture was then heated at 80 ° C. for 20 minutes. Upon cooling, the precipitate (AgBr) was removed by filtration. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was then washed with water, dried (Na ₂ SO ₄ ), concentrated and further dried under vacuum (0.01 mmHg). The title compound was used without further purification.

新たに調製したモルヒネ3(500mg、1.75mmol)、ジシクロヘキシルカルボジイミド(362mg、1.75mmol)、および5-ニトラト吉草酸4(286mg、1.75mmol)をアルゴン雰囲気下、無水クロロホルム(90mL)に溶解した。混合物を12時間還流させ、冷却させた。追加のジシクロヘキシルカルボジイミド(362mg、1.75mmol)、および5-ニトラト吉草酸(286mg、1.75mmol)を添加し、6時間還流を続けた。冷却すると、溶媒を真空で除去し、残渣を温めた酢酸エチル/メタノール(6:4)(〜5mL)溶液に溶解し、濾過し、N,N-ジシクロヘキシル尿素を除去した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー(酢酸エチル/メタノール；6:4)にかけると、モルヒネ誘導体5が淡黄色固体として得られる(600mg、80%)。

(c) Morphine NO donor

Freshly prepared morphine 3 (500 mg, 1.75 mmol), dicyclohexylcarbodiimide (362 mg, 1.75 mmol), and 5-nitratovaleric acid 4 (286 mg, 1.75 mmol) were dissolved in anhydrous chloroform (90 mL) under an argon atmosphere. The mixture was refluxed for 12 hours and allowed to cool. Additional dicyclohexylcarbodiimide (362 mg, 1.75 mmol) and 5-nitratovaleric acid (286 mg, 1.75 mmol) were added and reflux was continued for 6 hours. Upon cooling, the solvent was removed in vacuo and the residue was dissolved in warm ethyl acetate / methanol (6: 4) (˜5 mL) solution and filtered to remove N, N-dicyclohexylurea. The filtrate is concentrated and subjected to silica gel column chromatography (ethyl acetate / methanol; 6: 4) to give the morphine derivative 5 as a pale yellow solid (600 mg, 80%).

Tartrate salt of morphine NO donor 5 Compound 5 (300 mg, 0.697 mmol) was suspended in water (RO type) (15 mL), and tartaric acid (105 mg, 0.697 mmol) was added. The mixture was stirred for 30 minutes, after which dimethyl sulfoxide (AR grade) (15 mL) was added. The resulting solution was stored at -20 ° C.

標題化合物を、EP 0 984 012 A2(K.M.Lundy, M.T.Clark)の手順に従い調製した。簡単に言うと、5-ニトラト吉草酸(13.34g、0.082mol)を高真空(0.01mmHg)下、予め乾燥させ、その後、アルゴ雰囲気下、無水ジクロロメタン(200mL)に溶解した。これに五塩化リン(17.03g、0.082mol)を少しずつ2分にわたり添加した。混合物を15時間室温で撹拌した。溶媒および過剰の塩酸を真空で除去し、残渣を無水トルエンに溶解した。その後、トルエンを、アルゴン下、大気圧で蒸留させることにより90%除去した。[警告：蒸留により完全にトルエンを除去させてはいけないが、これは自然に爆発的分解が起きるためである]トルエンは、オキシ塩化リンの除去に不可欠である。トルエン酸塩化物混合物をさらに精製せずに使用した。 Example 3
Preparation of morphine-nitric oxide conjugate 7
5-Nitratovaleroyl chloride

The title compound was prepared according to the procedure of EP 0 984 012 A2 (KMLundy, MTClark). Briefly, 5-nitratovaleric acid (13.34 g, 0.082 mol) was pre-dried under high vacuum (0.01 mmHg) and then dissolved in anhydrous dichloromethane (200 mL) under an argon atmosphere. To this was added phosphorus pentachloride (17.03 g, 0.082 mol) in portions over 2 minutes. The mixture was stirred for 15 hours at room temperature. The solvent and excess hydrochloric acid were removed in vacuo and the residue was dissolved in anhydrous toluene. Subsequently, 90% of the toluene was removed by distillation at atmospheric pressure under argon. [Warning: Do not allow toluene to be completely removed by distillation, because it will spontaneously explode.] Toluene is essential for removing phosphorus oxychloride. The toluene acid chloride mixture was used without further purification.

モルヒネ塩酸塩三水和物(50mg、0.133mmol)および5-ニトラトバレロイルクロリド6(169mg、0.931mmol)を一緒にストレートで135℃で、7分間加熱すると、均一混合物が得られた。冷却すると、液体をジクロロメタン(10mL)で希釈し、飽和炭酸水素ナトリウム溶液(20mL)を含む分液漏斗に移した。数回洗浄した後、有機層を乾燥させ(Na₂SO₄)、蒸発させた。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/メタノール、グラジエント)にかけると、モルヒネNO供与体7が褐色油として得られた。

Morphine NO donor

Morphine hydrochloride trihydrate (50 mg, 0.133 mmol) and 5-nitratovaleroyl chloride 6 (169 mg, 0.931 mmol) were heated together straight at 135 ° C. for 7 minutes to give a homogeneous mixture. Upon cooling, the liquid was diluted with dichloromethane (10 mL) and transferred to a separatory funnel containing saturated sodium bicarbonate solution (20 mL). After washing several times, the organic layer was dried (Na ₂ SO ₄ ) and evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate / methanol, gradient) to give morphine NO donor 7 as a brown oil.

オキシコドン塩酸塩(1.5g)を、最小量の水(RO型)(〜20mL)に溶解し、これに、十分な飽和炭酸水素ナトリウムを添加し、溶液のpHを約11まで上昇させ、オキシコドンを沈殿させた。オキシコドン8を真空濾過により収集し、蒸留水(20mL)により、続いて少量の冷ジエチルエーテル(5mL)により洗浄した。白色固体を、アルミニウム箔で遮光し、高真空下(0.01mmHg)に3時間置いた。 Example 4
Preparation of oxycodone- nitric oxide conjugate 9 Oxycodone

Dissolve oxycodone hydrochloride (1.5 g) in a minimum amount of water (RO type) (~ 20 mL), add enough saturated sodium bicarbonate to raise the pH of the solution to about 11, and Precipitated. Oxycodone 8 was collected by vacuum filtration and washed with distilled water (20 mL) followed by a small amount of cold diethyl ether (5 mL). The white solid was shielded from light with aluminum foil and placed under high vacuum (0.01 mmHg) for 3 hours.

新たに調製したオキシコドン8(500mg、1.59mmol)、ジシクロヘキシルカルボジイミド(327mg、1.59mmol)、および5-ニトラト吉草酸4(259mg、1.59mmol)をアルゴン雰囲気下、無水クロロホルム(90mL)に溶解した。混合物を12時間還流させ、冷却させた。追加のジシクロヘキシルカルボジイミド(327mg、1.59mmol)、および5-ニトラト吉草酸(259mg、1.59mmol)を添加し、6時間還流を続けた。冷却すると、溶媒を真空で除去し、残渣を温めた酢酸エチル(〜5mL)溶液に溶解し、濾過し、N,N-ジシクロヘキシル尿素を除去した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー(酢酸エチル/メタノール；グラジエント)にかけると、誘導体9が淡黄色固体として得られた。 Oxycodone NO donor

Freshly prepared oxycodone 8 (500 mg, 1.59 mmol), dicyclohexylcarbodiimide (327 mg, 1.59 mmol), and 5-nitratovaleric acid 4 (259 mg, 1.59 mmol) were dissolved in anhydrous chloroform (90 mL) under an argon atmosphere. The mixture was refluxed for 12 hours and allowed to cool. Additional dicyclohexylcarbodiimide (327 mg, 1.59 mmol) and 5-nitratovaleric acid (259 mg, 1.59 mmol) were added and reflux was continued for 6 hours. Upon cooling, the solvent was removed in vacuo and the residue was dissolved in warm ethyl acetate (˜5 mL) solution and filtered to remove N, N-dicyclohexylurea. The filtrate was concentrated and subjected to silica gel column chromatography (ethyl acetate / methanol; gradient) to give derivative 9 as a pale yellow solid.

Oxycodone-nitrogen monoxide conjugate tartrate The compound 9 (300 mg, 0.651 mmol) was suspended in water (RO type) (15 mL) and tartaric acid (98 mg, 0.651 mmol) was added. The mixture was stirred for 30 minutes, after which dimethyl sulfoxide (AR grade) (15 mL) was added. The resulting solution was stored at -20 ° C.

Example 5
Assessment of antinociceptive response using the Tail Flick Latency Test <br/> Animals Adult male Sprague-Dawley rats (225-250 g) were tested in Herston Medical Research Centre, The University of Queensland (Brisbane (Australia), and adult male Sprague-Dawley rats were purchased from the University of Central Animal Breeding House, The University of Queensland (Brisbane, Australia). Rats were housed in a temperature controlled environment (21 ± 2 ° C.) using a 12 h / 12 h light / dark cycle. Food and water were unlimited. Ethical approval for this study was obtained from the Animal Experimentation Ethics Committee at Queensland University.

Reagents and Materials Morphine hydrochloride powder (BP) was purchased from Royal Brisbane Hospital Pharmacy (Brisbane, Australia). Standard saline ampules were obtained from Delta West Pty Ltd (Perth, Australia) and medical grade CO ₂ and O ₂ were purchased from BOC Gases Ltd (Brisbane, Australia).

Stock Solution Preparation Stock solutions of compound (2) and morphine HCl were prepared in standard saline to achieve final concentrations of 10 μmol / mL and 35 μmol / mL, respectively. An aliquot of the stock solution was stored at -20 ° C until needed.

Drug administration
While lightly anesthetized with a 50%: 50% mixture of O ₂ : CO ₂ , rats were given (2) (0.04 nmol / kg), morphine (2.8 μmol / kg [? ED ₂₀ ], 10 μmol / Either a single bolus dose of kg) or a combination of the two was administered via the subcutaneous (sc) route. Antinociceptiveness was quantified using the tail flick test over a 6 hour post-dose period.

Assessment of antinociceptive response using tail-flick latency testAntinociceptiveness was quantified in rats using tail-flick latency test (D'Amour and Smith, 1941, J. Pharmacol. Exp. And Ther., 72: 74-79). This included the application of harmful heat stimuli to the lower third of the ventral surface of the rat's tail. Prior to drug administration, baseline tail flick responses were measured at 5-minute intervals until three baseline latencies within ± 1 s were obtained (only three readings were needed in most rats, Only 5 were needed in rats). A maximum tail flick latency of 9.0 s was used to minimize tissue damage to the rat tail. The tail flick test was performed at the following times: 0.08, 0.25, 0.5, 0.45, 1, 1.5, 2, 3, 4, 6 hours after administration).

*ここで、最大テイルフリック潜時は9.0sである。
抗侵害受容性レベル(%MPE値)を、時間に対しプロットし、応答(%MPE)対時間曲線を作成した。 Data Analysis Raw tail flick latency values obtained from each rat were normalized by converting to a percentage of the maximum possible effect (% MPE; Brady and Holtzmann, Pharmacol. Exp. Ther., 1982, 222: 190- 7) ：

* Here, the maximum tail flick latency is 9.0s.
The antinociceptive level (% MPE value) was plotted against time to generate a response (% MPE) versus time curve.

  The percentage of area under the MPE vs. time curve (% MPE AUC) was calculated using trapezoidal integration.

Statistical analysis
The Mann-Whitney test was used to compare the differences in normalized% MPE AUC values between treatment groups. Statistical analysis was initiated using the GraphPad Prism ™ (version 3) software package, with a statistical significance criterion of P <0.05.

Antinociceptive efficacy of Compound 2 against noxious heat stimuli The antinociceptive efficacy of Compound 2 (from Example 1) alone and in combination with morphine was applied to the tail of naïve rats by applying a noxious heat (heating) stimulus (tail). The rat acute pain model was evaluated, including the flick test (FIG. 1). After administering a small sc bolus dose of 2 (0.04 nmol / kg) in combination with ~ ED ₂₀ morphine (2.8 μmol / kg), maximum pain relief (anti-nociceptive) occurs 45 minutes after administration, The duration of action was 3-4 hours. In contrast, when a single sc bolus dose of 2 (0.04 nmol / kg) or morphine (2.8 μmol / kg) alone was administered to rats, the peak level of antinociception was very low, i.e., respectively, The maximum possible effect (% MPE) was 14% and 21%, and the corresponding duration of action was considerably shorter in the range of 1.5-2 hours (FIG. 1). In summary, these low doses of 2 (0.04 nmol / kg) co-administered with morphine greatly increased the degree and duration of antinociception, which is a concomitant increase in CNS side effects such as sedation. Woke up without.

  The disclosures of all patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety.

  Citation of any reference herein shall not be construed as an admission that such reference is available as “Prior Art” to the present application.

  Throughout the specification the aim is to describe the preferred embodiments of the invention and is not intended to limit the invention to any one embodiment or specific collection of features. Thus, those skilled in the art will recognize in light of the present disclosure that various modifications and changes may be made in the particular embodiments illustrated without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.

Figure 2 is a graph showing the antinociceptive efficacy of morphine for noxious stimuli in untreated rats. A single subcutaneous (sc) bolus dose of morphine (white triangles) administered at 10 μmol / kg provides near-maximal pain relief from an adverse heat stimulus in 1 hour using the tail flick test. With ED ₂₀ doses of morphine (2.8 μmol / kg sc) (black triangle), only 20% of the maximum pain relief is obtained. An ED ₂₀ dose of morphine (2.8 μmol / kg sc), administered in combination with a 0.04 nmol / kg sc dose of a sustained release nitric oxide donor, Compound 2, produces maximal pain relief within 1 hour ( White diamonds) do not provide significant pain relief (black diamonds) when Compound 2 alone is administered (0.04 nmol / kg sc).

Claims (31)

  A method of producing an analgesic effect in a subject comprising administering to the subject an effective amount of a nitric oxide donor and an effective amount of an opioid analgesic, wherein the effective amount of nitric oxide donor is 0.0002 nmol. A method of delivering nitric oxide at a rate of between / kg / hour and 2.0 nmol / kg / hour.   2. The method of producing analgesic action in a subject according to claim 1, wherein the nitric oxide donor is formulated in a sustained release formulation.   2. The method for producing an analgesic effect in a subject according to claim 1, wherein the nitric oxide donor is a sustained release nitric oxide donor.   4. The method of producing an analgesic effect in a subject according to claim 3, wherein the effective amount of the nitric oxide donor is in the range of 0.004 nmol / kg to 0.4 nmol / kg.   2. The method of producing an analgesic effect in a subject according to claim 1, wherein the effective amount of the opioid analgesic is a sub-analgesic amount.   A method of producing an analgesic effect in a subject comprising administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and a subanalgesic amount of an opioid analgesic. A method of producing an analgesic effect in a subject comprising administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and an effective amount of an opioid analgesic, comprising: A method wherein the nitric oxide donor releases nitric oxide in the form of NO ⁺ or NO 2 ^— .   A method of producing an analgesic effect in a subject comprising administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and an effective amount of an opioid analgesic, comprising: A method wherein the nitric oxide donor enhances endogenous production of nitrosothiol.   A method of producing an analgesic effect comprising the steps of administering an effective amount of a sustained release nitric oxide donor or a sustained release formulation of a nitric oxide donor and an effective amount of an opioid analgesic, comprising providing nitric oxide A method by which the body reduces the endogenous production of peroxynitrite.   A method of producing an analgesic effect comprising the steps of administering an effective amount of a sustained release nitric oxide donor or a sustained release formulation of a nitric oxide donor and an effective amount of an opioid analgesic, comprising providing nitric oxide A method in which the body causes more endogenous production of nitrosothiols than endogenous production of peroxynitrite.   Opioid analgesics are morphine, methadone, fentanyl, sufentanil, alfentanil, hydromorphone, oxymorphone, oxycodone, codeine, hydrocodeine, hydrocodone, levorphanol, meperidine, heroin, morphine-6-glucuronide, levalorphan, 6-monoacetyl 11. A method according to any one of claims 1 to 10 selected from morphine and tramadol.   11. A method according to any one of claims 3 to 10, wherein the sustained release nitric oxide donor comprises a nitrato group attached to the carrier compound by a linker. 11. The method according to any one of claims 3 to 10, wherein the sustained release nitric oxide donor is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Where
R ¹ is OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
R ² and R ³ are each H or together become —O—;
R ⁴ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

And R ⁵ is H, or R ⁴ and R ⁵ together form an oxo group;
R ⁶ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

In which W is absent or -O-, -S-, -NH-, -NC _1-6 alkyl,

Selected from;
R ⁷ is C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkyl CO, C _1-20 alkyl SO, C _1-20 alkyl SO ₂ , aryl, aryloxy, aryl SO ₂ , aryl SO, aryl Selected from CO, N (R ⁸ ) ₂ , (R ⁸ ) ₂ NCO;
Each R ⁸ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl or aryl;
Each R is _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, aryl, heterocyclyl, halo, hydroxy, _C1-20 alkoxy, aryloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, heterocyclyloxy, thiol, C _{1 to 20} alkyl thiol, C _{2 to 20} alkenyl thiol, C _{2 to 20} alkynyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ R ' _{, SOR ', SO 2 R'} , SO 3 R ', SON (R') 2, SO 2 N (R ') 2, SO 3 N (R') 2, CON (R ') 2, N (R' ) ₂ , P (R ′) ₃ , P (═O) (R ′) ₃ , Si (R ′) ₃ , B (R ′) ₂ C _1-20 alkyl, CN, CF ₃ or NO ₂ Wherein each R ′ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, aryl and heterocyclyl;
m is 0 or an integer from 1 to 10;
n is an integer from 1 to 10; and
t is 0 or an integer from 1 to 4;
At least one of R ¹ , R ⁴ and R ⁶ is -OAX-NO ₂ ,

It is. 14. The method of claim 13, wherein the sustained release nitric oxide donor is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

Where
R ¹⁰ is OH, OCH ₃ , -OAX-NO ₂ ,

Selected from;
R ⁴⁰ is -OAX-NO ₂ ,

And R ⁵⁰ is H or R ⁴⁰ and R ⁵⁰ together form an oxo group;
R ⁶⁰ is H or -OAX-NO _2,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

In which W is absent or -O-, -S-, -NH-,

Selected from;
R ⁷⁰ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl CO, C _1-6 alkyl SO, C _1-6 alkyl SO ₂ , phenyl, phenoxy, phenyl SO, phenyl SO ₂ , phenyl CO N (R ⁸⁰ ) ₂ and (R ⁸⁰ ) ₂ NCO;
Each R ⁸⁰ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl;
Each R is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heterocyclyl, halo, hydroxy, C _1-6 alkoxy, aryloxy, C _2-6 alkenyloxy, heterocyclyloxy , Thiol, C _1-6 alkyl thiol, C _2-6 alkenyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ H, CO ₂ C _1-6 alkyl, SOC _1-6 Alkyl, SO ₂ C _1-6 alkyl, SO ₃ H, SO ₃ C _1-6 alkyl, SONH ₂ , SONHC _1-6 alkyl, SON (C _1-6 alkyl) ₂ , SO ₂ NH ₂ , SO ₂ NHC _{1 6 alkyl,} SO ₂ N (C 1~6 alkyl) _2, CONH _2, CONHC 1~6 alkyl, CON (C _{1 to 6} alkyl) _2, NH _2, NHC 1~6 alkyl, N (C _{1 to 6} Alkyl) ₂ , CN, CF ₃ or NO ₂ independently selected;
u is 0 or an integer from 1 to 5;
v is an integer from 1 to 5; and
t is 0 or an integer from 1 to 4;
At least one of R ¹⁰ , R ⁴⁰ and R ⁶⁰ is -OAX-NO ₂ ,

It is. The method for producing an analgesic action according to any one of claims 3 to 14, wherein the sustained-release nitric oxide donor is selected from the group consisting of:

  A method of alleviating pain comprising administering an effective amount of a nitric oxide donor and an effective amount of an opioid analgesic, wherein the nitric oxide donor is a sustained release nitric oxide donor, or A method that is formulated into a sustained release formulation that delivers nitric oxide at a rate of 0.0002 nmol / kg / hr to 2.0 nmol / kg / hr.   A method of alleviating pain comprising administering an effective amount of a sustained release nitric oxide donor or sustained release formulation of a nitric oxide donor, and a sub-analgesic amount of an opioid analgesic.   Opioid analgesics are morphine, methadone, fentanyl, sufentanil, alfentanil, hydromorphone, oxymorphone, oxycodone, codeine, hydrocodeine, hydrocodone, levorphanol, meperidine, heroin, morphine-6-glucuronide, levalorphan, 6-monoacetyl 18. A method according to claim 16 or 17 selected from morphine and tramadol.   19. The method of any one of claims 16-18, wherein the sustained release nitric oxide donor comprises a nitrato group attached to the carrier compound by a linker. 20. The method according to any one of claims 16 to 19, wherein the sustained release nitric oxide donor is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Where
R ¹ is OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
R ² and R ³ are each H or together become —O—;
R ⁴ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

And R ⁵ is H, or R ⁴ and R ⁵ together form an oxo group;
R ⁶ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

In which W is absent or -O-, -S-, -NH-, -NC _1-6 alkyl,

Selected from;
R ⁷ is C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkyl CO, C _1-20 alkyl SO, C _1-20 alkyl SO ₂ , aryl, aryloxy, aryl SO ₂ , aryl SO, aryl Selected from CO, N (R ⁸ ) ₂ , (R ⁸ ) ₂ NCO;
Each R ⁸ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl or aryl;
Each R is _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, aryl, heterocyclyl, halo, hydroxy, _C1-20 alkoxy, aryloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, heterocyclyloxy, thiol, C _{1 to 20} alkyl thiol, C _{2 to 20} alkenyl thiol, C _{2 to 20} alkynyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ R ' _{, SOR ', SO 2 R'} , SO 3 R ', SON (R') 2, SO 2 N (R ') 2, SO 3 N (R') 2, CON (R ') 2, N (R' ) ₂ , P (R ′) ₃ , P (═O) (R ′) ₃ , Si (R ′) ₃ , B (R ′) ₂ C _1-20 alkyl, CN, CF ₃ or NO ₂ Wherein each R ′ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, aryl and heterocyclyl;
m is 0 or an integer from 1 to 10;
n is an integer from 1 to 10; and
t is 0 or an integer from 1 to 4;
At least one of R ¹ , R ⁴ and R ⁶ is -OAX-NO ₂ ,

It is. 21. The method of claim 20, wherein the sustained release nitric oxide donor is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

Where
R ¹⁰ is OH, OCH ₃ , -OAX-NO ₂ ,

Selected from;
R ⁴⁰ is -OAX-NO ₂ ,

And R ⁵⁰ is H or R ⁴⁰ and R ⁵⁰ together form an oxo group;
R ⁶⁰ is H or -OAX-NO _2,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

In which W is absent or -O-, -S-, -NH-,

Selected from;
R ⁷⁰ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl CO, C _1-6 alkyl SO, C _1-6 alkyl SO ₂ , phenyl, phenoxy, phenyl SO, phenyl SO ₂ , phenyl CO N (R ⁸⁰ ) ₂ and (R ⁸⁰ ) ₂ NCO;
Each R ⁸⁰ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl;
Each R is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heterocyclyl, halo, hydroxy, C _1-6 alkoxy, aryloxy, C _2-6 alkenyloxy, heterocyclyloxy , Thiol, C _1-6 alkyl thiol, C _2-6 alkenyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ H, CO ₂ C _1-6 alkyl, SOC _1-6 Alkyl, SO ₂ C _1-6 alkyl, SO ₃ H, SO ₃ C _1-6 alkyl, SONH ₂ , SONHC _1-6 alkyl, SON (C _1-6 alkyl) ₂ , SO ₂ NH ₂ , SO ₂ NHC _{1 6 alkyl,} SO ₂ N (C 1~6 alkyl) _2, CONH _2, CONHC 1~6 alkyl, CON (C _{1 to 6} alkyl) _2, NH _2, NHC 1~6 alkyl, N (C _{1 to 6} Alkyl) ₂ , CN, CF ₃ or NO ₂ independently selected;
u is 0 or an integer from 1 to 5;
v is an integer from 1 to 5; and
t is 0 or an integer from 1 to 4;
At least one of R ¹⁰ , R ⁴⁰ and R ⁶⁰ is -OAX-NO ₂ ,

It is. The method for producing an analgesic effect according to any one of claims 16 to 21, wherein the sustained-release nitric oxide donor is selected from the group consisting of:

  The pain is selected from the group consisting of moderate to severe cancer pain, moderate to severe postoperative pain, post-traumatic pain, pain associated with myocardial infarction, and inflammatory pain. 23. The method according to any one of 22. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

Where
R ¹ is OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
R ² and R ³ are each H or together become —O—;
R ⁴ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

And R ⁵ is H, or R ⁴ and R ⁵ together form an oxo group;
R ⁶ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

Wherein either W are not present, or -O -, - S -, - NH -, - NC 1~6 alkyl,

Selected from;
R ⁷ is C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkyl CO, C _1-20 alkyl SO, C _1-20 alkyl SO ₂ , aryl, aryloxy, aryl SO ₂ , aryl SO, aryl Selected from CO, N (R ⁸ ) ₂ , (R ⁸ ) ₂ NCO;
Each R ⁸ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl or aryl;
Each R is _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, aryl, heterocyclyl, halo, hydroxy, _C1-20 alkoxy, aryloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, heterocyclyloxy, thiol, C _{1 to 20} alkyl thiol, C _{2 to 20} alkenyl thiol, C _{2 to 20} alkynyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ R ' _{, SOR ', SO 2 R'} , SO 3 R ', SON (R') 2, SO 2 N (R ') 2, SO 3 N (R') 2, CON (R ') 2, N (R' ) ₂ , P (R ′) ₃ , P (═O) (R ′) ₃ , Si (R ′) ₃ , B (R ′) ₂ C _1-20 alkyl, CN, CF ₃ or NO ₂ Wherein each R ′ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, aryl and heterocyclyl;
m is 0 or an integer from 1 to 10;
n is an integer from 1 to 10; and
t is 0 or an integer from 1 to 4;
At least one of R ¹ , R ⁴ and R ⁶ is -OAX-NO ₂ ,

It is. 25. The compound of claim 24, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

Where
R ¹⁰ is OH, OCH ₃ , -OAX-NO ₂ ,

Selected from;
R ⁴⁰ is -OAX-NO ₂ ,

And R ⁵⁰ is H or R ⁴⁰ and R ⁵⁰ together form an oxo group;
R ⁶⁰ is H or -OAX-NO _2,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

In which W is absent or -O-, -S-, -NH-,

Selected from;
R ⁷⁰ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl CO, C _1-6 alkyl SO, C _1-6 alkyl SO ₂ , phenyl, phenoxy, phenyl SO, phenyl SO ₂ , phenyl CO N (R ⁸⁰ ) ₂ and (R ⁸⁰ ) ₂ NCO;
Each R ⁸⁰ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl;
Each R is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heterocyclyl, halo, hydroxy, C _1-6 alkoxy, aryloxy, C _2-6 alkenyloxy, heterocyclyloxy , Thiol, C _1-6 alkyl thiol, C _2-6 alkenyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ H, CO ₂ C _1-6 alkyl, SOC _1-6 Alkyl, SO ₂ C _1-6 alkyl, SO ₃ H, SO ₃ C _1-6 alkyl, SONH ₂ , SONHC _1-6 alkyl, SON (C _1-6 alkyl) ₂ , SO ₂ NH ₂ , SO ₂ NHC _{1 6 alkyl,} SO ₂ N (C 1~6 alkyl) _2, CONH _2, CONHC 1~6 alkyl, CON (C _{1 to 6} alkyl) _2, NH _2, NHC 1~6 alkyl, N (C _{1 to 6} Alkyl) ₂ , CN, CF ₃ or NO ₂ independently selected;
u is 0 or an integer from 1 to 5;
v is an integer from 1 to 5; and
t is 0 or an integer from 1 to 4;
At least one of R ¹⁰ , R ⁴⁰ and R ⁶⁰ is -OAX-NO ₂ ,

It is. 25. The compound of claim 24, selected from the group consisting of:

A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent:

Where
R ¹ is OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
R ² and R ³ are each H or together become —O—;
R ⁴ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

And R ⁵ is H, or R ⁴ and R ⁵ together form an oxo group;
R ⁶ is H, OH, OC _1-6 alkyl, -OAX-NO ₂ ,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

Wherein either W are not present, or -O -, - S -, - NH -, - NC 1~6 alkyl,

Selected from;
R ⁷ is C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkyl CO, C _1-20 alkyl SO, C _1-20 alkyl SO ₂ , aryl, aryloxy, aryl SO ₂ , aryl SO, aryl Selected from CO, N (R ⁸ ) ₂ , (R ⁸ ) ₂ NCO;
Each R ⁸ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl or aryl;
Each R is _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, aryl, heterocyclyl, halo, hydroxy, _C1-20 alkoxy, aryloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, heterocyclyloxy, thiol, C _{1 to 20} alkyl thiol, C _{2 to 20} alkenyl thiol, C _{2 to 20} alkynyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ R ' _{, SOR ', SO 2 R'} , SO 3 R ', SON (R') 2, SO 2 N (R ') 2, SO 3 N (R') 2, CON (R ') 2, N (R' ) ₂ , P (R ′) ₃ , P (═O) (R ′) ₃ , Si (R ′) ₃ , B (R ′) ₂ C _1-20 alkyl, CN, CF ₃ or NO ₂ Wherein each R ′ is independently selected from H, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, aryl and heterocyclyl;
m is 0 or an integer from 1 to 10;
n is an integer from 1 to 10; and
t is 0 or an integer from 1 to 4;
At least one of R ¹ , R ⁴ and R ⁶ is -OAX-NO ₂ ,

It is. 28. A pharmaceutical composition according to claim 27 comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof:

Where
R ¹⁰ is OH, OCH ₃ , -OAX-NO ₂ ,

Selected from;
R ⁴⁰ is -OAX-NO ₂ ,

And R ⁵⁰ is H or R ⁴⁰ and R ⁵⁰ together form an oxo group;
R ⁶⁰ is H or -OAX-NO ₂ ,

Selected from;
-------------- indicates a single bond or a double bond;
X represents O or S;
Y represents _{O, S, SO, SO 2} , CO, CONH, a CO _2, NH or NC _{1 to 6} alkyl;
Z represents _{SO, SO 2, CO, CONH} , a CO _2, NH or NC _{1 to 6} alkyl;
A indicates:

In which W is absent or -O-, -S-, -NH-,

Selected from;
R ⁷⁰ is C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl CO, C _1-6 alkyl SO, C _1-6 alkyl SO ₂ , phenyl, phenoxy, phenyl SO, phenyl SO ₂ , phenyl CO N (R ⁸⁰ ) ₂ and (R ⁸⁰ ) ₂ NCO;
Each R ⁸⁰ is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or aryl;
Each R is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heterocyclyl, halo, hydroxy, C _1-6 alkoxy, aryloxy, C _2-6 alkenyloxy, heterocyclyloxy , Thiol, C _1-6 alkyl thiol, C _2-6 alkenyl thiol, aryl thiol, heterocyclyl thiol, benzyl, benzyloxy, benzylthio, acyl, acyloxy, CO ₂ H, CO ₂ C _1-6 alkyl, SOC _1-6 Alkyl, SO ₂ C _1-6 alkyl, SO ₃ H, SO ₃ C _1-6 alkyl, SONH ₂ , SONHC _1-6 alkyl, SON (C _1-6 alkyl) ₂ , SO ₂ NH ₂ , SO ₂ NHC _{1 6 alkyl,} SO ₂ N (C 1~6 alkyl) _2, CONH _2, CONHC 1~6 alkyl, CON (C _{1 to 6} alkyl) _2, NH _2, NHC 1~6 alkyl, N (C _{1 to 6} Alkyl) ₂ , CN, CF ₃ or NO ₂ independently selected;
u is 0 or an integer from 1 to 5;
v is an integer from 1 to 5; and
t is 0 or an integer from 1 to 4;
At least one of R ¹⁰ , R ⁴⁰ and R ⁶⁰ is -OAX-NO ₂ ,

It is. 28. The pharmaceutical composition of claim 27, comprising a compound selected from the group consisting of:

  30. The pharmaceutical composition according to any one of claims 27 to 29, further comprising an opioid analgesic.   Opioid analgesics include morphine, methadone, fentanyl, sufentanil, alfentanil, hydromorphone, oxymorphone, oxycodone, codeine, hydrocodeine, hydrocodone, levorphanol, meperidine, heroin, morphine-6-glucuronide, levalorphan, 6-monoacetyl 31. A pharmaceutical composition according to claim 30, selected from morphine and tramadol.

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